Purpose: Triple immunosuppressant therapy with cyclosporine (CsA), prednisone, and azathioprine has been the mainstay of initial maintenance immunosuppression for renal transplantation in the U.S. These drugs have different mechanisms of action and different toxicities. Many patients do well with only two immunosuppressant agents late after renal transplantation, however, there are no controlled comparative trials of the withdrawal of immunosuppressant agents. The primary hypothesis is that withdrawal of cyclosporine in stable renal allograft recipients 12 months or more after transplantation results in a slower decline in renal function and less interstitial fibrosis than withdrawal of either mycophenylate or prednisone. Methods: This is an open label, randomized, controlled, therapeutic comparison trial, limited to patients at low risk for acute rejection following a decrease in immunosuppression. Cadaveric and living renal transplant recipients > 18 yr old with at most one acute rejection episode within the first three months after transplant and no subsequent episodes, and stable renal function for 9 months prior to entry will be eligible. Patients with more than 500 mg of protein excretion/24 hr will be excluded as will those unable to continue one of the three drugs. All patients will have been treated with standard maintenance immunosuppression during the first year after transplantation. At 12 months patients will be receiving MMF (1 g bid), Neoral or Sandimmune (CsA), and prednisone. Patients will be randomly allocated to 3 groups. Enrollment will occur 12-36 months after renal transplantation and follow-up will be for 2 years for evaluation of renal function and 5 years for those patients who agree to undergo allograft biopsies at baseline and 5 years after withdrawal. A sample size of 258 enrolled at four centers over 3 years will allow the detection of a difference of 2 ml/min/yr between the three groups. Patients allocated to group I will undergo withdrawal of CsA over 12 weeks, with a transient increase in the prednisone dose at the time of CsA cessation. Patients allocated to group II will undergo prednisone withdrawal over 12 weeks, with CsA levels maintained in the high end of the usual target range for 3 months after withdrawal of prednisone. Patients allocated to group III will undergo MMF withdrawal over 12 weeks. At 12, 18, 24, 30 and 36 months after transplantation patients will have a physical exam, standard laboratory tests, and a GFR measurement using iohexol clearance. Prior to randomization, patients will also be asked to participate in the biopsy portion of the study. Patients who elect to participate in the biopsy study will undergo a protocol biopsy immediately after randomization and prior to immunosuppression withdrawal. Patients who have acute rejection on the biopsy will be dropped from the study before any reduction in immunosuppression, and will not be considered in the final analysis. If at any time it appears likely that a patient (who has not already had an adequate biopsy within the previous six months) may return to chronic, maintenance dialysis therapy, a second protocol biopsy will be obtained. Otherwise, 6 years after transplantation patients with functioning allografts will be asked to undergo a second protocol biopsy. All protocol biopsies will be scored blindly by a renal pathologist using the Banff criteria. In addition, a detailed morphometric analysis will be carried out on all biopsies. The primary endpoint is the rate of decline in GFR as measured by the slope of serial GFR determinations (minimum of 2) made between 18 and 36 months after transplantation. For patients who return to dialysis before the 18th month post-transplant, the slope will be based on the baseline and final GFR determinations. Results: To date 10 patients have been enrolled locally and approximately 50 total by all centers. An interim analysis has not yet been completed. Significance: When the entire study is completed, we will be able to better guide immunosuppressive therapy in renal transplant recipients and hopefully be better able to limit the amount of expensive and potentially toxic medication given to these patients.